It is often presumed that high frequency ventilation (HFV) with low tidal volumes (smaller than anatomic dead space) produces lower alveolar pressures than conventional mechanical ventilation, thus reducing the attendant risks of barotrauma and diminished cardiac output. However, in a preliminary modeling study, we found that this presumption is not always valid. We propose a series of experiments on dogs to test the model prediction and to further our understanding of the interaction between gas transport and lung mechanics during HFV. We will determine the optimal combination of HFV parameters that would simultaneously maximize gas exchange and minimize alveolar pressures. The parameters in question are frequency, tidal volume, airflow waveform and lung volume. We will investigate how respiratory optimization is affected under certain simulated disease conditions. We will also compare the effects of applying HFV by external chest oscillation with the more common mode of HFV application via the trachea. From our measurements of gas transport, local airway transport resistances and lung mechanical characteristics, we will develop a mathematical model that incorporates both the gas exchange and lung mechanics aspects of HFV, including important nonlinearities such as gas trapping. This model will be used to generate clinically significant predictions of how respiratory function may best be optimized in human adults and infants with pulmonary disease.